Acute lymphoblastic leukemia (ALL) is the most prevalent childhood cancer, although it also occurs in adults. Current treatment strategies often result in overtreatment for some patient groups, causing severe long-term side effects, while other patients exhibit therapy resistance or develop relapse. Individuals with relapsed disease or treatment-related complications generally have significantly worse clinical outcomes. Consequently, there is a strong need for biomarkers that can guide the selection of more effective and individualized targeted therapies. Our recent studies have demonstrated that integrating quantitative proteomics, advanced thermal proteome profiling, and drug-response analyses can uncover unexpected subtype-specific therapeutic vulnerabilities and more accurately reflect cellular phenotypes associated with drug sensitivity. In particular, we have improved the mechanistic understanding of bryostatin-1 as a promising targeted treatment option for high-risk MEF2D-rearranged ALL. Our findings indicate that bryostatin-1 activates the MAPK signaling pathway while simultaneously modulating TCF3 and MYC activity through epigenetic mechanisms, suggesting a dual mode of action. Building on these findings, we now aim to evaluate these therapeutic strategies in more clinically relevant systems through integrated multi-omics analyses of 30 patient-derived xenograft (PDX) models, 145 clinical ALL samples, 137 ALL cell lines and 700 RNA-seq samples data from public resources. By incorporating structural variant analysis, epigenetic profiling from whole genome sequencing (WGS), and post-translational modification data at the proteome level, we aim to further improve biomarker discovery and mechanistic understanding. Altogether, this project and the resulting large-scale resource will expand our knowledge of ALL biology and support the development of precision medicine approaches that can improve treatment outcomes for ALL patients.